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Neonatal Abstinence Syndrome Lauritz Meyer, MD September 11, 2015 SDPA Conference.

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Neonatal Abstinence Syndrome Lauritz Meyer, MD September 11, 2015 SDPA Conference

Neonatal Abstinence Syndrome

Neonatal Abstinence SyndromeLauritz Meyer, MDSeptember 11, 2015SDPA Conference

DisclosureI have no financial relationships to disclose.ObjectivesDescribe the incidence of Neonatal Abstinence Syndrome in the United StatesIdentify common symptoms of Neonatal Abstinence SyndromeFamiliarize with scoring systems for Neonatal Abstinence SyndromeIdentify treatment strategies for Neonatal Abstinence SyndromeNeonatal Abstinence SyndromeDefined as a group of clinical signs and symptoms in a neonate resulting from prolonged exposure to illicit or prescribed drugsAlso called Neonatal Drug WithdrawalShort term syndrome but may have long lasting effectsCan be caused by in-utero exposure or iatrogenic exposure in hospitalized neonatesOpiate HistoryOpium derived from the poppyFirst records of opium addiction are from the late 18th centuryIncrease in opioid addiction among women noted in the 19th century

Opiate HistoryMorphine isolated in 1804Use among women was associated with sterility

Heroin synthesized in 1874Initially thought addiction among women did not affect infants

Opiate History1875: first reported case of neonatal abstinenceMore over years, most died, no specific treatment1903: First report of neonate surviving abstinence after Tx with morphineCalled Congenital Morphinism1947: Seizures in a baby with Congenital Morphinism were successfully treated with morphineLed to increased awareness and name changed to Abstinence Syndrome in NeonatesOpiate HistoryMethadone:Introduced in 1964 as a replacement treatment for opioid addictionMethadone clinics became very common for treating recovering heroin addictsInitially thought to not cause withdrawal in neonates, likely secondary to increased half life but since has become a common cause of NAS

Opiate HistoryBuprenorphine:Approved as an alternative to methadone for opioid addiction in U.S. in 2002Sublingual tabletsAlso leads to NASMay cause less severe NAS symptoms than methadone

Illicit Drug Use in the U.S.2013 National Survey on Drug Use and Health9.4% of population age 12 and older used illicit drugs within the past month (24.6 million individuals)5.4% of pregnant women aged 15-44 were current illicit drug users14.6% in age 15-17 year olds9% in the first trimester4.8% in the second trimester2.4% in the third trimester22.9% of population age 12 and older were binge alcohol users in the past month (60.1 million individuals)6.3% were defined as heavy drinkers9.4% of pregnant women were current alcohol users, 2.3% were binge drinkers, and 0.4% were heavy drinkersIllicit Drug Use in the Upper Midwest2013 National Survey on Drug Use and HealthSouth Dakota6.17% of 12 years and older have used illicit drugs in the past month (42 thousand individuals)Minnesota7.63% of 12 years and older have used illicit drugs in the past month (343 thousand individuals)Iowa7.34% of 12 years and older have used illicit drugs in the past month (188 thousand individuals)Incidence of NASRisingIncidence has nearly doubled in the past 15 years based on national ICD-9 codingBecoming more widespreadNo longer just inner citiesIncreased use of prescription pain medications in pregnant womenImproved recognition of NASNAS Causing DrugsOpioidsMorphine, Methadone, Hydromorphone, Fentanyl, HeroinCNS DepressantsBenzodiazepines, Alcohol, BarbituratesCNS StimulantsAmphetamines, Cocaine, Nicotine, CaffeineHallucinogensLSD, inhalants, mescalinePolysubstance useSSRIsOpioidsAmong the worlds oldest known drugsUse of opium poppy goes back milenniaThree types: natural, endogenous, and syntheticProduces analgesia by binding to mu-opioid receptors in the CNS, PNS, and GI systemLeads to inhibition of noradrenaline releaseEffects include:SedationEuphoriaRespiratory depressionDecreased GI motilityLong term use leads to physical dependenceOpioidsWithdrawalThe initial condition that led to the diagnosis of NASAbrupt discontinuation leads to:Massive release of noradrenalineLeads to autonomic, behavioral, and GI symptoms/signsTiming, presentation, and severity of symptoms dependent upon maternal and neonatal factorsDrug, dosage, time since last use, placental transfer, metabolismMu-opioid receptor (OPRM1) and catechol-o-methyltransferase (COMT) gene genetic variations affect the need for and the length of treatmentOpioidsNeonates exposed in-utero have signs/symptoms of opioid withdrawal 55-94% of the timeAddition of other maternal or neonatal medications, neonatal diet, and environmental stimuli can affect the severity and incidence of NASSymptoms can present within the first 24 hours of life, or be delayed for 7 days or longerDependent on type of drug, metabolism, etc.Clinical Symptoms of NAS due to OpioidsGastrointestinalVomiting/diarrheaPoor feedingUncoordinated suckConstant suckingDehydrationPoor weight gain/FTT

AutonomicExcessive sweatingTemperature instabilityNasal stuffinessMottlingYawningNeurologicTremorsIrritabilityIncreased wakefulnessHigh-pitched cryHypertonicity Hyperactive reflexesExaggerated MoroSeizuresFrequent sneezing/yawningVideohttps://www.youtube.com/watch?v=2eP5EnFSG0cClinical Symptoms (cont.)Seizures occur in 2-11 percent of NAS casesEEG abnormalities have been seen in up to 30% of NAS cases attributed to opioidsIncreased incidence of Small for Gestational Age (SGA) birthsIncreased incidence of respiratory difficultiesTiming of WithdrawalWide variation dependent upon the half-life of the drug and the recent history of drug useSymptoms can present within the first 24 hours for short half life drugs (Heroin), but may not present for 72 hours up to 7 days or longer for long half life drugs (Methadone, Buprenorphine)Neonates born to mothers who have gone >7 days from last use are at much lower risk for NAS, but still require close monitoringMethadoneCommon prescription drug used for recovering Heroin addictsLong half life leads to delayed presentation of NAS symptoms for several daysHigher daily doses are more likely to lead to NAS>95% of infants will develop symptoms with doses >20mg/dayDifficult to wean mothers during pregnancy due to high risk of fetal complications with abrupt dose changes

BuprenorphineIncreasing use for opiate withdrawal including during pregnancyLower transplacental transfer due to higher molecular weightThought to lower the incidence and severity of NASDecreased length of stay for infants with NASSubutex buprenorphine onlySuboxone buprenorphine plus naloxone to guard against misuse

FentanylUse of transdermal patch increasing for treatment of chronic painShort half life leads to rapid symptoms of NAS in the first 24 hoursRisk of rapid withdrawal for mother if lose access to supply of patchesBreastfeeding a concern due to risk of rapid withdrawal

DepressantsAlcohol withdrawal can present 3-12 hours after birthMay show symptoms of NAS similar to opioid withdrawal although usually more mildBenzodiazepine withdrawal can have a variable onset dependent upon half life and dosage

StimulantsMethamphetamine and cocaine have low rates of NAS requiring therapySymptoms at birth more likely the result of drug effects vs withdrawalSimilar symptoms to opioid NAS tremors, irritability, poor sleep pattern, excessive sucking, etcHigh rates of prematurity and IUGR statusIncreased risk of placental abruptionCommon to see polysubstance useSSRIsUsed in 7-13% of pregnancies10-30% risk of Poor Neonatal Adaptation SyndromeTremors, increased tone, high pitched cry, poor sleep patterns are common symptomsIncreased rate of respiratory distressIncreased risk of PPHNGenerally presents in the first 48 hours of life and resolve within another 48 hoursParoxetine (Paxil) carries the highest risk

Withdrawal vs ToxicityWithdrawal:Symptoms develop as the amount of drug decreases, indicative of dependence on the drugMost common with opioids, but also with depressants and SSRIsToxicity:Symptoms present early and decrease as the drug is metabolizedMost common with stimulants such as cocaine or methamphetaminePremature InfantsLower risk of developing NAS 8 suggest careful monitoring and likely need for pharmacotherapyLipsitzAssigns a score of 0 to 3 for tremors, irritability, reflexes, stools, muscle tone, skin abrasions, and tachypneaAssigns a score of 0 to 1 for frequent sneezing, frequent yawning, and vomiting or feverA score of 5 or greater suggests opiate exposureA score of 8 or greater indicates need for pharmacotherapyTreatmentGoals of treatment:Allow the infant to withdraw without excessive excitation that can lead to withdrawal symptomsEspecially important to avoid the most severe, i.e. seizuresEstablish a physiologic sleep patternEstablish consistent weight gainAllow the infant to communicate needs with caregiversHelp the infant manage new stimuli in its new environmentNon-pharmacologic TreatmentFirst line therapy is ALWAYS non-pharmacologicRequired for all infants with suspected NASKeep environmental stimulation to a minimumLow lightQuiet environmentSwaddlingGentle handling with cares/cluster caresQuick response to symptomsDemand feeding***Cuddlers***

Non-pharmacologic treatmentMany large centers with a high population of NAS cases have a specific section or completely separate NICU dedicated to the care of NAS babiesNursing care with experience in caring for NAS babies is crucial to help ensure a safe and swift recoveryPharmacotherapyDecision to initiate pharmacotherapy based on abstinence scoring and the known or suspected drug exposureIndicated when non-pharmacologic treatment is insufficientIndicated for moderate/severe symptomsRequired to prevent severe complications, i.e. seizures

PharmacotherapyDrawbacks:Increases length of drug exposureIncreases length of stayMay impact maternal-infant bonding as a result

Benefits:Decreases the acute signs of NASDecreases the risk of severe complications like seizures or failure to thrivePharmacotherapyIdeally treat with the same class of drug as that causing NASChoice can be a challenge when drug of exposure is unknown or in setting of polysubstance use

PharmacotherapyMainstay of therapy has been opioidsOpioids are first line treatment based on available evidenceHistoric use of tincture of opium and paregoric have fallen out of favor due to safety concernsMorphine and Methadone are the two most common opioids used to treat NASBuprenorphine is a potential option but limited safety and efficacy data in neonatesSublingual dosing appealPharmacotherapy - MorphineVariety of dosing regimens available for MorphineHigh dose0.08-0.1 mg/kg every 4 hours POLow dose0.03-0.04 mg/kg every 4 hours POWith either regimen, the dose may be increased by 20% every 8 hours until symptoms are well controlledTypical maximum dose is 0.2 mg/kg/doseOther regimens include escalation by changing to every 3 hour dosingPharmacotherapy - MorphineWeaning is individualized to each patientTypical approach is to maintain current dose when adequate symptom control is achievedAfter 48-72 hours of stability may begin weaningWean by decreasing dose by 20% every other dayMay require delayed taper or escalation if symptoms worsenPharmacotherapy - MethadoneTypical starting dose of 0.05-0.1 mg/kg every 6 hours POAdjust doses up and down by ~20% as needed similar to MorphineMay require less frequent adjustments since half life is longer and effects of dose changes may be slower to manifest than with Morphine2nd Line TreatmentUsed for severe NAS that is not controlled with a first line agentPhenobarbital Most commonly used second line drugDiazepam First line if the known cause of NAS is a benzodiazepineClonidine Used to avoid the sedative effects of phenobarbitalPhenobarbitalPreferred medication for non-opiate NASGABA agonistDoes not prevent seizures at typical NAS dosesMinimal benefit for GI symptomsUsual dose: 16 mg/kg loading dose, then 2-8 mg/kg/day divided BID for maintenanceRoute: Oral, IV, or IMContinue treatment until Morphine or Methadone are weaned off before weaning phenobarbitalTaper phenobarbital by 10-20% per day

DiazepamRequires caution due to limited capacity of infants to metabolizeContains sodium benzoateRequires monitoring for jaundice as it may displace bilirubin for conjugation and excretionInitial dose 1-2 mg every 8-12 hoursMay also consider lorazepam or midazolam dependent on preference and experienceClonidineEffective adjunctive medication with opioids in shortening the duration of treatmentCentrally acting alpha adrenergic agonistRequires monitoring for hypotension and bradycardiaInitial dose 0.5-1 mcg/kg followed by 3-5 mcg/kg/day divided every 4-6 hoursRequires taper due to risk of hypertension and tachycardia with abrupt discontinuation

NaloxoneContraindicated in the treatment of NAS due to the risk for rapid and severe NAS symptomsMay precipitate seizures in some neonates

Iatrogenic NASTreat with same drug class that was used for pain control/sedationCalculate total daily cumulative dose and divide into a schedule of equivalent medicationDo not forget PRN doses!!Nutrition and NASMay have increased metabolic demandsMay require significant increase in kcal/kg/day to offset losses from NASFortified feedsAd lib demand schedule Prompt response to hunger cues importantMay be frequent, small volume feedersRequires close monitoring of weight gain/loss and fluid status Vomiting and loose stools may lead to increased fluid requirementsPO intake may be poor NNG supplementation or IV hydrationBreastfeedingLow rates of breastfeeding among NAS affected neonatesAAP supports breastfeeding in appropriate situationsMay help with withdrawal symptomsRequires strict adherence and review of risks and benefits with the mother before initiationBreastfeeding AllowedOk to breastfeed when mothers are on a stable dose of methadone or buprenorphineLow doses excreted in breastmilkMothers who are in a treatment program prior to delivery or are enrolled into a program at birthRequires strict adherence to the program with continued close follow upNo other contraindications to breastfeedingBreastfeeding ContraindicationsPolysubstance abuse or history of non-adherence to treatment programsHIV or other infectious riskMothers taking hydrocodone or oxycodoneRequire closer monitoring as these drugs are highly excreted in breastmilkAny illicit drug use during the 30 day period prior to deliveryBreastfeedingBest to follow strict feeding protocols to ensure a similar amount of breastmilk is provided each dayHave mothers pump and provided pumped breastmilk early on to ensure consistent volumesProvide for 1-2 feeds on day 1, and gradually increase as supply increases over the following daysDiscontinuation of breastfeedingImportant to stress weaning off of breastmilk as abrupt discontinuation may precipitate NAS symptoms at that timeDischarge and Follow UpInfants at risk for NAS require in-hospital monitoring until past the window for severe withdrawalDependent upon the drug exposureWith known history of short half life drugs such as morphine or hydrocodone, may be discharged after 72 hoursWith known history of long half life drugs such as methadone, may be discharged after 5-7 daysFollow up visit should be scheduled within 2 days of discharge to ensure continued close monitoringDischarge after TreatmentInfants requiring pharmacotherapy:Discharge frequently delayed until fully weaned off of medications with an adequate observation period off pharmacotherapy to ensure no rebound NASDischarge while still on therapy is an option if parents are reliable, taper is easily followed, and adequate follow up is assuredExtensive education about non-pharmacologic measures for treatment of symptoms and strict criteria for seeking evaluation are vital at dischargePrenatal CounselingImportant to be empathetic and nonjudgementalTeratogenicityOpioids and stimulants can cause SGA status, prematurity, abruption, SABCocaine and methamphetamine may lead to long term neurodevelopmental issuesExpected Clinical CourseObservation for at least 3-7 days for signs and symptoms of NASNon-pharmacologic therapy is the primary treatmentPharmacotherapy will require treatment that may last weeks to months

Prenatal CounselingBreastfeedingBreastfeeding may be suitable in certain situations dependent upon the drugs usedBreastfeeding may help decrease NAS symptomsHelpful to have a breastfeeding plan prior to deliverySocial ConcernsVital to discuss the importance of caregiver involvement in treatment of NASAdherence to follow up schedule and treatment recommendations will be vital to outcomesTake Home PointsNAS is a common condition in newborns and the incidence is risingClose monitoring is vital for infants at risk of NASInfants who demonstrate symptoms without known risk factors require evaluation for NASNon-pharmacologic measures are the first line therapy for NASBreastfeeding is not contraindicated in NAS in some situations and can be beneficial in NAS treatmentReferencesAverys Diseases of the Newborn, 9th Ed. 2012Burgos A, Burke B. Neonatal Abstinence Syndrome. NeoReviews. 2009;10(5)e222-229.Kocheriakota P. Neonatal Abstinence Syndrome. Pediatrics. 2014;134(2):e547-561.Tolia V, Patrick S, Bennett M, et al. Increasing Incidence of the Neonatal Abstinence Sydrome in the U.S. Neonatal ICUs. NEJM. 2015;372(22)2118-2126.Jansson L. Neonatal abstinence syndrome. UpToDate. 2015.Patrick S, Davis M, Lehman C, Cooper W. Increasing incidence and geographic distribution of neonatal abstinence syndrome: United States 2009-2012. J Perinatology. 2015. 1-6.2013 National Survey on Drug Use and Health. http://www.samhsa.gov/data/population-data-nsduh